Influenced by Lincoln Steffens, his career began when he was nineteen years old and was hired at the Pittsburgh Leader. In 1914, he was appointed night editor of the Pittsburgh Post.

In 1916, he went to the United Press in London and, starting in 1917, during World War I, he moved to France to work at the Marshall Syndicate. While there, he interviewed Paul von Hindenburg, the supreme commander of the German Army. Hindenburg commented on the defeat of Germany in the war, including U.S. involvement; however this interview was censored by the U. S. military. Seldes would later comment that the publishing of this interview could have avoided the rising of the Nazis to power and, thus, World War II.

After World War I, he spent ten years as a reporter for the Chicago Tribune. In 1922, he interviewed Vladimir Lenin and, in 1923, got expelled from the Soviet Union, along with three colleagues, for disguising news reports as personal letters; a letter his publisher wrote for the Soviets only facilitated his expulsion. The newspaper then sent him to Italy, where he reported on opposition leader Giacomo Matteotti's murder, implicated Benito Mussolini in Matteotti's death, and was again expelled.

In 1927, he reported for the Chicago Tribune in Mexico, where he criticized the use of the country's mineral rights by American companies. He battled with the Tribune's owner and publisher, Col. Robert McCormick, over the paper's altering of his Mexico articles, and soon afterwards quit the Tribune over what he felt was censorship. v In 1929, Seldes became a freelance reporter and author, subsequently writing a series of books and criticisms about his years as a foreign correspondent, and the issues of censorship, suppression and distortion in the press. During the late 1930s he had one more stint as a foreign correspondent, along with his wife Helen, for the New York Post, in Spain during the Spanish Civil War.

In 1940, Seldes co-founded a weekly newsletter, In Fact, subtitled "an Antidote to Falsehoods in the Daily Press." In it, he attacked corporate malfeasance, often using governmental documents from the Federal Trade Commission (FTC) and the Federal Communications Commission (FCC). He exposed, issue after issue, the health hazards of cigarettes and attacked the mainstream press for suppressing such news, blaming the newspapers' heavy dependence on cigarette advertising. He cited J. Edgar Hoover and the FBI for anti-union campaigns. He brought attention to how the National Association of Manufacturers was able to use its advertising dollars to produce news stories favorable to its members and to suppress news stories unfavorable to them.

Having both staunch admirers and strong critics, Seldes influenced many younger journalists. He received an award for professional excellence from the Association for Education in Journalism in 1980,[3] and a George Polk Award for his life's work in 1981. Seldes also served on the board of Fairness and Accuracy in Reporting (FAIR).